Roadmap for direct and indirect translation of optogenetics into discoveries and therapies for humans

Optogenetics has transformed basic research on neural circuitry, led to diverse experimental insights into human brain function and dysfunction, and opened pathways for clinical translation based on new understanding of how specific cell types contribute to cognition and behavior. Many of these translational pathways do not rely on the direct application of optogenetics in humans, but rather develop and advance other treatment modalities by leveraging causal knowledge derived from optogenetic circuit neuroscience. However, a recent proof-of-principle study-showing that optogenetics applied directly to the human central nervous system can treat blindness-underscores not only the curative potential but also the need for careful ethical consideration in the extension of direct optogenetic intervention to other disorders. Here, we review relevant considerations-including the selection of clinical indications, identification of molecular and optical strategies for specificity, and navigation of safety and regulatory issues-that together inform the development of optogenetic translation targeting cells and circuits that have been causally implicated through optogenetic discoveries.